Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed By the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed By Surgery

This randomized phase II-R/III trial studies gemcitabine hydrochloride with or without erlotinib hydrochloride followed by the same chemotherapy regimen with or without radiation therapy and capecitabine or fluorouracil in treating patients with pancreatic cancer that was removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, capecitabine, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells. Giving chemotherapy together with or without erlotinib hydrochloride and/or radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether chemotherapy is more effective when given with or without erlotinib hydrochloride and/or radiation therapy in treating pancreatic cancer.

Overall survival (Phase II) [ Time Frame: From the date of first randomization (gemcitabine vs. gemcitabine/erlotinib) to the date of death or last follow-up, assessed up to 11 years ] [ Designated as safety issue: No ]

Overall survival will be estimated by the Kaplan-Meier method. The distribution of overall survival estimates between the two arms for both primary endpoint questions will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with overall survival.

Overall survival (Phase III) [ Time Frame: From the date of second randomization (chemotherapy vs. chemotherapy followed by chemoradiation) to the date of death or last follow-up, assessed up to 11 years ] [ Designated as safety issue: No ]

Overall survival will be estimated by the Kaplan-Meier method. The distribution of overall survival estimates between the two arms for both primary endpoint questions will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with overall survival.

Secondary Outcome Measures:

Changes in fatigue as measured by the FACIT-F (primary) and the PROMIS derived short form (exploratory) [ Time Frame: Baseline up to 24 months ] [ Designated as safety issue: No ]

The primary HRQoL hypothesis will be tested using the log-rank statistic with a significance level of 0.05. Additionally, analyses of fatigue effect will be performed using the Cox proportional hazard model.

Disease-free survival [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]

Disease-free survival will be estimated by the Kaplan-Meier method.

Frequency of objective criteria of resectability as measured by preoperative imaging [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]

Incidence of adverse events assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 11 years ] [ Designated as safety issue: Yes ]

Patients receive gemcitabine hydrochloride as in arm I and erlotinib hydrochloride PO once daily on days 1-28. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Drug: Erlotinib Hydrochloride

Given PO

Other Names:

Cp-358,774

ERLOTINIB HYDROCHLORIDE

OSI-774

Tarceva

Drug: Gemcitabine Hydrochloride

Given IV

Other Names:

dFdCyd

Difluorodeoxycytidine Hydrochloride

GEMCITABINE HYDROCHLORIDE

Gemzar

LY-188011

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Quality-of-Life Assessment

Ancillary studies

Other Name: Quality of Life Assessment

Experimental: Arm III (chemotherapy)

Patients receive 1 course of the same treatment that they receive in arm I or II.

Drug: Erlotinib Hydrochloride

Given PO

Other Names:

Cp-358,774

ERLOTINIB HYDROCHLORIDE

OSI-774

Tarceva

Drug: Gemcitabine Hydrochloride

Given IV

Other Names:

dFdCyd

Difluorodeoxycytidine Hydrochloride

GEMCITABINE HYDROCHLORIDE

Gemzar

LY-188011

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Quality-of-Life Assessment

Ancillary studies

Other Name: Quality of Life Assessment

Experimental: Arm IV (chemotherapy, chemoradiotherapy)

Patients receive 1 course of the same treatment that they receive in arm I or II. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO BID 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed.

I. To determine whether the addition of erlotinib (erlotinib hydrochloride) to gemcitabine (gemcitabine hydrochloride) adjuvant chemotherapy shows a signal for improved survival as compared to gemcitabine alone following R0 or R1 resection of head of pancreas adenocarcinoma (including adenocarcinoma of the head, neck, and uncinate process). (Phase II-R) II. To determine whether the use of concurrent fluoropyrimidine and radiotherapy following adjuvant gemcitabine hydrochloride-based chemotherapy further enhances survival for such patients who are without evidence of progressive disease after 5 cycles of gemcitabine based chemotherapy. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate disease-free survival of adjuvant chemotherapy followed by radiotherapy and concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who are disease free after 5 cycles of adjuvant chemotherapy.

II. To evaluate disease-free survival of standard adjuvant gemcitabine chemotherapy with and without erlotinib for patients with resected head of pancreas adenocarcinoma.

III. To evaluate adverse events with and without erlotinib for patients with resected head of pancreas adenocarcinoma.

IV. To evaluate adverse events of adjuvant chemotherapy with or without radiation therapy and concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma who are disease free after adjuvant chemotherapy.

V. To evaluate preoperative cross-sectional imaging of the primary head of pancreas adenocarcinoma in order to determine the frequency with which objective criteria of resectability are present.

VI. To determine if patients reporting low baseline fatigue, as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, predicts survival and to explore correlations between baseline fatigue, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS), and survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Patients with no disease progression after treatment in arm I or II are then stratified according to their first randomization treatment arm (arm I vs arm II) and randomized to 1 of 2 additional treatment arms (arm III or IV).

ARM III: Patients receive 1 course of the same treatment that they receive in arm I or II.

ARM IV: Patients receive 1 course of the same treatment that they receive in arm I or II. Beginning within 7-21 days after completion of chemotherapy, patients undergo radiotherapy (3-dimensional conformal radiotherapy or intensity-modulated radiotherapy) 5 days per week for 5.5 weeks (28 fractions). During radiotherapy, patients receive either capecitabine PO twice daily (BID) 5 days per week or fluorouracil IV continuously for 5.5 weeks or until radiotherapy is completed.

After completion of study treatment, patients are followed up periodically.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Histologic proof of primary head of pancreas invasive adenocarcinoma managed with a potentially curative resection (i.e., removal of all gross tumor) involving a classic pancreaticoduodenectomy (Whipple) or a pylorus preserving pancreaticoduodenectomy; patients with invasive adenocarcinoma that also contains a component of intraductal papillary mucinous neoplasm (IPMN) are eligible

The operating surgeon must document in the operative note that a complete gross excision of the primary tumor was achieved; the pathology report must include documentation of the margin status and the size of the tumor; the pathology report must also include the status of the three major margins—bile duct, pancreatic parenchyma, and retroperitoneal (uncinate)

Interval between definitive tumor-related surgery and 1st step registration between 21-70 days

Patients will be staged according to the 6th edition American Joint Committee on Cancer (AJCC) staging system with pathologic stage T1-3, N0-1, M-0 being eligible

Zubrod performance status 0 or 1

Complete history and physical examination including weight and Zubrod status within 31 days of study entry

Before starting therapy the patient should be able to maintain adequate oral nutrition of >= 1500 calories estimated caloric intake per day and be free of significant nausea and vomiting

Serum total bilirubin =< twice the institutional upper limit of normal (ULN) within 21 days of registration on study

Creatinine levels =< twice the institutional upper limit of normal within 21 days of registration on study

Serum glutamic oxaloacetic transaminase (SGOT) must be =< 2.5 x institutional ULN within 21 days of registration on study

Negative serum pregnancy test for women of childbearing potential within 14 days of study registration

Abdominal/pelvic computed tomography (CT) scan with contrast is preferred; abdominal CT alone is acceptable only if insurance restrictions are experienced; chest CT/x-ray (CT of chest preferred) within 31 days of registration on study; patients allergic to intravenous (IV) contrast can have magnetic resonance imaging (MRI) of the abdomen/pelvis instead

Signed study-specific informed consent

Consultation, agreement, and documentation in the patient's chart by a radiation oncologist that patient is suitable to receive radiotherapy per this protocol

Patients with active human immunodeficiency virus (HIV) infection are eligible if their cluster of differentiation (CD)4 count is > 499/cu mm and their viral load is < 50 copies/ml; use of highly active antiretroviral treatment (HAART) is allowed

Exclusion Criteria:

Patients with non-adenocarcinomas, adenosquamous carcinomas, islet cell (neuroendocrine) tumors, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct, and ampullary carcinomas; patients with tumors that are largely IPMN with a minimal or minor component of invasive carcinoma are not eligible; patients with acinar carcinomas are not eligible; patients with IPMN's that contain some secondary (minor) foci of adenocarcinoma are also not eligible

Patients managed with a total pancreatectomy, a distal pancreatectomy, or central pancreatectomy

Prior systemic chemotherapy for pancreas cancer; note that prior chemotherapy for a different cancer is allowable

Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

Previous history of invasive malignancy (except non-melanoma skin cancer) unless the patient has been disease free for at least 2 years prior to study entry (patients with a previous history of carcinoma in situ are eligible)

Transmural myocardial infarction within the 3 months of study registration

Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

Pregnant or lactating women

Women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

If surgical margin status cannot be determined after consultation with the operating surgeon and the institutional pathologist, the patient will be ineligible

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01013649